Erythropoietin, a cytokine made in the kidney, has proven to be effective therapy for anemia in patients with end-stage renal disease. The tissue distribution and regulation of gene expression for erythropoietin and its receptor reveal important insight on erythropoietin induction by hypoxia, on its role in mature red cell production and its activity in non-hematopoietic tissues. Erythropoietin acts primarily to regulate blood hemoglobin through the formation of mature red blood cells and binds to its receptor on the surface of erythroid progenitor cells to promote erythropoiesis by preventing apoptosis and stimulating proliferation and differentiation. Mice that lack erythropoietin or its receptor die in utero from severe anemia. To determine the role of endogenous erythropoietin beyond erythropoiesis, we examined mice with erythropoietin receptor expression restricted to hematopoietic tissue. These animals survived through adulthood with normalized erythroid differentiation and hematocrit, and exhibited no gross morphologic deformation. We observed that these mice exhibit an age dependent obesity with an increase in body weight up to twice that of wild type animals at 12 months. These mice eventually became insulin resistance with a significant increase in weight gain, principally in white fat. Erythropoietin also affected adipogenesis in culture. These observations suggest that erythropoietin may contribute to maintaining fat mass accumulation and provide new insight to the consequence of erythropoietin activity in non-hematopoietic cells.